A pilot study designed to test the feasibility of photoactivatable analogs of natural enediyne antitumor antibiotics is proposed. We will modify the enediyne core of the molecule responsible for the cytotoxicity of these natural products, making it inactive in the dark but readily activatable by light. To achieve this goal we plan to explore a novel mode of photoactivation, the in situ generation of active enediyne fragment. This will be done by employing two strategies: 1) the photochemical ring contraction of eleven-membered ring enediynes and 2) the in situ photochemical formation of pi-component of the enediyne conjugated system. Four photochemical reactions known to provide a high quantum yield of the products will be examined as enediyne activators: 1) photo-Wolff reaction of alpha-diazodicarbonyl compounds; 2) decarbonylation of cyclopropenones; 3) Norrish type II cleavage of alpha-diketones; and 4) photochemical ligand exchange in ruthenium complexes. We plan to explore the suitability of the above reactions for enediyne activation and the stability of corresponding precursors. We will then synthesize cyclic enediynes incorporating selected photoreactive moieties and investigate their photoactivation and DNA cleavage abilities. The most active systems will be conjugated with a DNA-binding molecule for the in vitro testing of photonuclease efficiency. The results of this investigation are expected to serve as a basis for the development of new photoactivatable enediyne anticancer agents. These compounds should be non-toxic in the dark but be selectively activated in the target tissue by light of an appropriate wavelength. Since the simultaneous presence of both photoactivatable antibiotics and light are required to develop cytotoxicity, damage to healthy tissues can be minimized.